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Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 9/30/2006 Publication Date: 10/3/2006 Citation: Boadu, E., Choi, H.Y., Lee, D.W., Waddington, E.I., Chan, T., Asztalos, B., Vance, J.E., Chan, A., Castro, G., Francis, G.A. 2006. Correction of Apolipoprotein A-I-mediated Lipid Efflux and High Density Lipoprotein Particle Formation in Human Niemann-Pick Type C Disease Fibroblasts. Journal of Biological Chemistry. 281(48):37081-37090. Interpretive Summary: Homozygous familial hypercholesterolemia (HoFH) is a rare disorder characterized by the early onset of atherosclerosis, often at the ostia of coronary arteries. In this study we document for the first time that aortic and coronary atherosclerosis can be detected using 64 slice multiple detector-row computed tomographic coronary angiography (CTCA). We studied 5 HoFH patients (3 females, 2 males, mean age 19.8 +/- 2.9 years, age range 15-23 years, with a mean low density lipoprotein (LDL) cholesterol 618 + 211 mg/dL)using 64 slice CTCA. None of the patients showed evidence of ischemia with standard exercise testing. Calcified and mixed atherosclerotic plaques adjacent to or compromising the coronary artery ostia were found in all study subjects. Coronary plaques causing significant obstruction were found in one patient, who had previously undergone coronary artery bypass surgery and aortic valve replacement. Two other patients were noted to have non-obstructive calcified, mixed and non-calcified coronary artery plaques. Our data suggest that CTCA could be a useful non-invasive method for detection of early aortic and coronary atherosclerosis specifically affecting the coronary ostia. Technical Abstract: Impaired cell cholesterol trafficking in Niemann-Pick type C (NPC) disease results in the first known instance of impaired regulation of the ATP-binding cassette transporter A1 (ABCA1), a lipid transporter mediating the rate-limiting step in high density lipoprotein (HDL) formation, as a cause of low plasma HDL-cholesterol in humans. We show here that treatment of human NPC1_/_fibroblasts with the liver X receptor (LXR) agonist TO-901317 increases ABCA1 expression and activity in humanNPC1_/_fibroblasts, as indicated by near normalization of efflux of radiolabeled phosphatidylcholine and a marked increase in efflux of cholesterol mass to apoA-I. LXR agonist treatment prior to and during apoA-I incubation resulted in reduction in filipin staining of unesterified cholesterol in late endosomes/lysosomes, as well as cholesterol mass, in NPC1_/_ cells. HDL species in human NPC disease plasma showed the same pattern of diminished large, cholesterol-rich_-1 HDL particles as seen in isolated heterozygous ABCA1 deficiency. Incubating NPC1_/_fibroblasts with the LXR agonist normalized the pattern of HDLparticle formation by these cells. ABCG1, another LXR target gene involved in cholesterol efflux to HDL, also showed diminished expression in NPC1_/_ fibroblasts and increased expression upon LXR agonist treatment. These results suggest that NPC1 mutations can be largely bypassed and that NPC1 protein function is non-essential for the trafficking and removal of cellular cholesterol if the downstream defects in ABCA1 and ABCG1 regulation in NPC disease cells are corrected using an LXR agonist. |
